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Other Infections

Cenicriviroc May Reduce Fibrosis in People with Fatty Liver Disease


Cenicriviroc, a drug that blocks both CCR5 and CCR2 receptors on immune cells, was associated with a decrease in liver fibrosis in people with non-alcoholic steatosis, a type of fatty liver disease, according to a report in the August 17 online edition of Hepatology.

Cenicriviroc did not reduce the severity of steatosis or liver inflammation any more than a placebo, but people in the cenicriviroc treatment group were significantly more likely to see a reduction in liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver disease worldwide. Often linked to obesity, the build-up of fat in the liver is associated with inflammation and development of scar tissue (fibrosis), which can interfere with normal liver function. Now that a vaccine can prevent hepatitis B and effective treatment can cure hepatitis C, fatty liver disease is expected to outpace viral hepatitis as a leading cause of cirrhosis and liver cancer. But to date there are no good treatments for NAFLD.

Cenicriviroc, being developed by Tobira Therapeutics, blocks CCR5, one of the coreceptors HIV uses to enter T-cells, and it was previously studied as an HIV treatment. It also interferes with CCR2, a cytokine that promotes migration of monocytes, and it has been found to have anti-inflammatory and anti-fibrotic activity. Kenneth Sherman of the University of Cincinnati and colleagues previously reportedthat HIV-positive people who received cenicriviroc for 2 years in an HIV treatment study saw a decrease in biomarkers of liver fibrosis.

Scott Friedman of the Icahn School of Medicine at Mount Sinai and colleagues conducted the CENTAUR study to evaluate cenicriviroc for the treatment of people with non-alcoholics steatohepatitis (NASH), the more severe form of NAFLD, accompanied by liver fibrosis.

This randomized, double-blind Phase 2b study enrolled nearly 300 participants with NASH and mild to severe (stages 1-3) liver fibrosis. NASH was defined as having a NAFLD activity score of 4 or higher. This scoring system takes into account the presence of large fat droplets in liver cells, inflammation of functional structures in the liver called lobules, and "ballooning" of liver cells.

Men and women were equally represented, 86% of participants were white, 16% identified as Hispanic, and the mean age was 54 years. Almost all (95%) were overweight with at least one criteria of metabolic syndrome, half had type 2 diabetes, and 38% had advanced liver fibrosis at baseline.

Participants were randomly assigned to receive 150 mg cenicriviroc or a placebo. The primary study outcome was at least a 2-point improvement in the NAFLD activity score with no worsening of fibrosis. Other outcomes included resolution of steatohepatitis (liver fat accumulation with inflammation), at least a 1-stage improvement in fibrosis, and changes in liver biopsies and liver stiffness according to FibroScan. Biomarkers of systemic inflammation were also measured.

After 1 year a similar proportion of study participants in both groups had at least a 2-point NAFLD score improvement in an intent-to-treat analysis -- 16% in the cenicriviroc arm and 19% in the placebo arm -- so the study did not meet its primary endpoint. The proportions who had a complete resolution of steatohepatitis was also statistically similar, 8% and 6%, respectively.

However, the researchers found that significantly more people in the cenicriviroc group compared with the placebo group saw at least a 1-point improvement in fibrosis with no worsening of steatohepatitis: 20% versus 10%, respectively. The improvement was greatest in people who started out with the worst inflammatory activity and fibrosis at baseline.

People taking cenicriviroc also had more marked decreases in systemic inflammation biomarkers including high-sensitivity C-reactive protein, interleukin-1-beta, interleukin-6, and fibrinogen. However, there was no significant change in lobule inflammation. Biopsies showed a reduction in collagen, a protein that makes up fibrotic scar tissue.

Cenicriviroc was generally safe and well-tolerated, with a similar distribution of adverse events in both treatment groups. There was only 1 possibly treatment-related serious adverse events (a heart arrhythmia). Grade 3-4 laboratory abnormalities were uncommon.

"After one year of cenicriviroc treatment, twice as many subjects achieved improvement in fibrosis and no worsening of steatohepatitis compared with placebo," the researchers concluded, adding that although the primary end point of the study was not met, these findings warrant further evaluation of the drug.

CENTAUR participants are now undergoing further follow-up in an open-label extension of the study. The Phase 3 AURORA studyof cenicriviroc for the treatment of liver fibrosis in people with NASH is currently enrolling participants.



SL Friedman, V Ratziu, SA Harrison, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. August 17, 2017 (online ahead of print).